This application claims the benefit of the filing date of German Patent Application No. 10060292.4, filed on Dec. 5, 2000, which application is hereby incorporated by reference.
The invention relates to substituted benzimidazoles of formula I: 
in which:
R1 and R5 are, independently of one another, F, Cl, Br, I, CN, alkyl having 1 to 4 carbon atoms, in which alkyl is unsubstituted or partially or completely substituted by fluorine; or
R1 and R5 are cycloalkyl having 3 to 7 carbon atoms, which is unsubstituted or partially or completely substituted by fluorine; or
R1 and R5 are, independently of one another, OH or O-alkyl having 1 to 4 carbon atoms, in which alkyl is unsubstituted or partially or completely substituted by fluorine; or
R1 and R5 are, independently of one another, OCOR10, NR11R12, COR13, COOH, COOR14, CONR11R12, or xe2x80x94(O)nxe2x80x94SOmR15, in which n is 0 or 1 and m is 0, 1, or 2; or
R1 and R5 are O-phenyl, in which phenyl is unsubstituted or substituted by one to three substituents selected, independently of one another, from F, Cl, Br, I, alkyl having 1 to 4 carbon atoms, OH, O-alkyl having 1 to 4 carbon atoms, NR16R17, CN, or (C1-C4)-alkylsulfonyl, in which the alkyl groups are unsubstituted or partially or completely substituted by fluorine;
R16 and R17 are, independently of one another, H or alkyl having 1 to 4 carbon atoms, in which alkyl is unsubstituted or partially or completely substituted by fluorine;
R10 is H or alkyl having 1 to 4 carbon atoms, in which alkyl is unsubstituted or partially or completely substituted by fluorine;
R11 and R12 are, independently of one another, H or alkyl having 1 to 4 carbon atoms, in which alkyl is unsubstituted or partially or completely substituted by fluorine, and at least one CH2 group of said alkyl is optionally replaced by O or NR18; or
R11 and R12, together with the nitrogen atom to which they are bonded, form a 5-, 6-, or 7-membered ring; or
R11 and R12 are, independently of one another, COR19 or SO2R20;
R18, R19, and R20 are, independently of one another, H or alkyl having 1 to 4 carbon atoms, in which alkyl is unsubstituted or partially or completely substituted by fluorine;
R13 and R14 are alkyl having 1 to 4 carbon atoms, which is unsubstituted or partially or completely substituted by fluorine;
R15 is alkyl or O-alkyl, in which the alkyl groups have 1 to 4 carbon atoms and are unsubstituted or partially or completely substituted by fluorine; or
R15 is OH or NR21 R22;
R21 and R22 are, independently of one another, H or alkyl having 1 to 4 carbon atoms, in which alkyl is unsubstituted or partially or completely substituted by fluorine, and at least one CH2 group of said alkyl is optionally replaced by O or NR23;
R23 is H or alkyl having 1 to 4 carbon atoms, in which alkyl is unsubstituted or partially or completely substituted by fluorine; or
R21 and R22, together with the nitrogen atom to which they are bonded, form a 5-, 6-, or 7-membered ring;
but R1 and R5 cannot simultaneously be Cl or CH3;
R2, R3, and R4 are H or one of the radicals R2, R3, or R4 is optionally F;
R6, R7, R8, and R9 are, independently of one another, H, F, Cl, Br, l, CN, alkyl, or O-alkyl, in which the alkyl groups have 1 to 4 carbon atoms and are unsubstituted or partially or completely substituted by fluorine; or
R6, R7, R8, and R9 are cycloalkyl having 3 to 7 carbon atoms, which is unsubstituted or partially or completely substituted by fluorine; or
R6, R7, R8, and R9 are, independently of one another, OH, OCOR24, or NR25R26;
R24 is H or alkyl having 1 to 4 carbon atoms, in which alkyl is unsubstituted or partially or completely substituted by fluorine;
R25 and R26 are, independently of one another, H or alkyl having 1 to 4 carbon atoms, in which alkyl is unsubstituted or partially or completely substituted by fluorine; or
R25 and R26 are COR27; or
R25 and R26, together with the nitrogen atom to which they are bonded, form a 5-, 6-, or 7-membered ring, and at least one CH2 group thereof is optionally replaced by O or NR18;
R27 is H or alkyl having 1 to 4 carbon atoms, in which alkyl is unsubstituted or partially or completely substituted by fluorine; or
a pharmaceutically tolerable salt or trifluoroacetate thereof.
Other embodiments of compounds of formula I are those in which:
R1 and R5 are, independently of one another, F, Cl, Br, CN, alkyl having 1 to 4 carbon atoms, CF3, CH2CF3, CF2CF3, cycloalkyl having 3 to 7 carbon atoms, O-alkyl having 1 to 4 carbon atoms, OH, OCF3, OCH2CF3, OCF2CF3, OCOR10, NR11R12, COR13, COOH, COOR14, CONR11R12, xe2x80x94Omxe2x80x94SO2R15, or O-phenyl;
m is 0 or 1;
R10 is H, alkyl having 1 to 4 carbon atoms, CF3, CH2CF3, or CF2CF3;
R11 and R12 are, independently of one another, H, alkyl having 1 to 4 carbon atoms, CF3, CH2CF3, CF2CF3, and at least one CH2 group of said alkyl is optionally replaced by O or NR18; or
R11 and R12, together with the nitrogen atom to which they are bonded, form a 5-, 6-, or 7-membered ring; or
R11 and R12 are, independently of one another, COR19 or SO2R20;
R18, R19, and R20 are, independently of one another, H, alkyl having 1 to 4 carbon atoms, CF3, CH2CF3, or CF2CF3;
R13 and R14 are, independently of one another, alkyl having 1 to 4 carbon atoms, CF3, CH2CF3, or CF2CF3;
R15 is alkyl having 1 to 4 carbon atoms, CF3, CH2CF3, CF2CF3, OH, O-alkyl having 1 to 4 carbon atoms, OCF3, OCH2CF3, OCF2CF3, or NR21R22;
R21 and R22 are, independently of one another, H, alkyl having 1 to 4 carbon atoms, CF3, CH2CF3, or CF2CF3; or
R21 and R22, together with the nitrogen atom to which they are bonded, are xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)5xe2x80x94, xe2x80x94(CH2)2xe2x80x94Oxe2x80x94(CH2)2xe2x80x94, or xe2x80x94(CH2)2xe2x80x94Nxe2x80x94R30xe2x80x94(CH2)2;
R30 is H, CH3, or CF3;
but R1 and R5 cannot simultaneously be Cl or CH3;
R2, R3, and R4 are H or one of the radicals R2, R3, or R4 is optionally F;
R6, R7, R8, and R9 are, independently of one another, H, F, Cl, Br, I, CN, alkyl having 1 to 4 carbon atoms, CF3, CH2CF3, CF2CF3, cycloalkyl having 3 to 7 carbon atoms, OH, O-alkyl having 1 to 4 carbon atoms, OCF3, OCH2CF3, OCF2CF3, OCOR24, or NR25R26;
R24 is H, alkyl having 1 to 4 carbon atoms, CF3, CH2CF3, or CF2CF3;
R25 and R26 are, independently of one another, H, alkyl having 1 to 4 carbon atoms, CF3, CH2CF3, CF2CF3, or COR27; or
R25 and R26, together with the nitrogen atom to which they are bonded, form a 5-, 6-, or 7-membered ring;
R27 is H, alkyl having 1 to 4 carbon atoms, CF3, CH2CF3, or CF2CF3; or
a pharmaceutically tolerable salt or trifluoroacetate thereof.
Another embodiment of compounds of formula I are those in which:
R1 and R5 are, independently of one another, F, Cl, Br, CN, methyl, ethyl, isopropyl, CF3, cyclopropyl, OH, O-methyl, O-ethyl, O-isopropyl, OCF3, O-acetyl, NH2, N(CH3)2, N(CH2CH3)2, N-pyrrolidino, N-piperidino, N-morpholino, N-(Nxe2x80x2-methyl)-piperazino, NHSO2Me, acetyl, COOH, COOR14, CONR11R12, SO2R15, or O-phenyl;
R11 and R12 are, independently of one another, H, methyl, or ethyl;
R14 is methyl or ethyl;
R15 is CH3, CF3, OH, OCH3, OCF3, or NR21R22;
R21 and R22 are, independently of one another, H or methyl;
but R1 and R5 cannot simultaneously be Cl or CH3;
R2, R3, and R4 are H;
R6, R7, R8, and R9 are, independently of one another, H, F, Cl, CN, CH3, C2H5isopropyl, CF3, cyclopropyl, OH, OCH3, OCF3, O-acetyl, or NR25R26;
R25 and R26 are, independently of one another, H, methyl, or acetyl; or
a pharmaceutically tolerable salt or trifluoroacetate thereof.
Another embodiment of compounds of formula I are those in which:
R1 and R5 are, independently of one another, F, Cl, Br, CN, methyl, ethyl, isopropyl, CF3, cyclopropyl, OH, O-methyl, O-ethyl, O-isopropyl, OCF3, O-acetyl, NH2, N(CH3)2, N(CH2CH3)2, N-pyrrolidino, N-piperidino, N-morpholino, N-(Nxe2x80x2-methyl)-piperazino, NHSO2Me, acetyl, COOH, COOR14, CONR11R12, SO2R15, or O-phenyl;
R11 and R12 are, independently of one another, H, methyl, or ethyl;
R14 is methyl or ethyl;
R15 is CH3, CF3, OH, OCH3, OCF3, or NR21R22;
R21 and R22 are, independently of one another, H or methyl;
but R1 and R5 cannot simultaneously be Cl or CH3;
R2, R3, and R4 are H;
R6 and R9 are, independently of one another, H, F, Cl, CN, CH3, CF3, cyclopropyl, OH, OCH3, OCF3, O-acetyl, or NR25R26;
R25 and R26 are, independently of one another, H, methyl, or acetyl;
R7 and R8 are, independently of one another, H, F, or OH; or
a pharmaceutically tolerable salt or trifluoroacetate thereof.
Examples of compounds of formula I are:
(1H-benzimidazol-2-yl)-(2,6-dichlorophenyl)amine;
2-(2,6-dichlorophenylamino)-1H-benzimidazol-4-ol;
(1H-benzimidazol-2-yl)-(2,6-dimethylphenyl)amine;
(1H-benzimidazol-2-yl)-(2-chloro-6-methylphenyl)amine;
(2,6-dichlorophenyl)-(5,6-difluoro-1H-benzimidazol-2-yl)amine;
(2,6-dichlorophenyl)-(4-methyl-1H-benzimidazol-2-yl)amine;
(1H-benzimidazol-2-yl)-(2-chloro-6-fluorophenyl)amine;
(1H-benzimidazol-2-yl)-(2,6-dibromophenyl)amine;
2-(2,6-dichlorophenylamino)-5-fluorobenzimidazole;
2-(2,6-dichlorophenylamino)-4-fluorobenzimidazole;
2-(2-trifluoromethyl-6-chlorophenylamino)benzimidazole;
2-(2,6-dichlorophenylamino)-4,5-difluorobenzimidazole;
2-(2,6-dichlorophenylamino)-5-hydroxybenzimidazole;
2-(2,6-dichlorophenylamino)-4,5,6,7-tetrafluorobenzimidazole;
2-(2,6-dichlorophenylamino)-4,6-difluorobenzimidazole;
(1H-benzimidazol-2-yl)-(2-chlorophenyl)amine;
(1H-benzimidazol-2-yl)-(2-trifluoromethylphenyl)amine;
(1H-benzimidazol-2-yl)-(2-bromophenyl)amine; and
(1H-benzimidazol-2-yl)-o-tolylamine; or
a pharmaceutically tolerable salt or trifluoroacetate thereof.
In addition, the invention comprises the use of substituted benzimidazoles of formula I for the production of a medicament for the treatment of diseases which are influenced by the NHE3 exchange inhibitor, in which:
R1 and R5 are, independently of one another, H , F, Cl, Br, I, CN, alkyl having 1 to 4 carbon atoms, in which alkyl is unsubstituted or partially or completely substituted by fluorine; or
R1 and R5 are cycloalkyl having 3 to 7 carbon atoms, which is unsubstituted or partially or completely substituted by fluorine; or
R1 and R5 are OH or O-alkyl having 1 to 4 carbon atoms, in which alkyl is unsubstituted or partially or completely substituted by fluorine; or
R1 and R5 are OCOR10, NR11R12, COR13, COOH, COOR14, CONR11R12, or xe2x80x94(O)nxe2x80x94SOmR15, in which n is 0 or 1 and m is 0, 1, or 2; or
R1 and R5 are O-phenyl, in which phenyl is unsubstituted or substituted by one to three substituents selected from F, Cl, Br, I, alkyl having 1 to 4 carbon atoms, OH, O-alkyl having 1 to 4 carbon atoms, NR16R17, CN, or (C1-C4)-alkylsulfonyl, in which the alkyl groups are unsubstituted or partially or completely substituted by fluorine;
R16 and R17 are H or alkyl having 1 to 4 carbon atoms, in which alkyl is unsubstituted or partially or completely substituted by fluorine;
R10 is H or alkyl having 1 to 4 carbon atoms, in which alkyl is unsubstituted or partially or completely substituted by fluorine;
R11 and R12 are, independently of one another, H or alkyl having 1 to 4 carbon atoms, in which alkyl is unsubstituted or partially or completely substituted by fluorine, and at least one CH2 group of said alkyl is optionally replaced by O or NR18; or
R11 and R12, together with the nitrogen atom to which they are bonded, form a 5-, 6-, or 7-membered ring; or
R11 and R12 are COR19 or SO2R20;
R18, R19, and R20 are, independently of one another, H or alkyl having 1 to 4 carbon atoms, in which alkyl is unsubstituted or partially or completely substituted by fluorine;
R13 and R14 are alkyl having 1 to 4 carbon atoms, which is unsubstituted or partially or completely substituted by fluorine;
R15 is alkyl or O-alkyl, in which the alkyl groups have 1 to 4 carbon atoms and are unsubstituted or partially or completely substituted by fluorine; or
R15 is OH or NR21R22;
R21 and R22 are, independently of one another, H or alkyl having 1 to 4 carbon atoms, in which alkyl is unsubstituted or partially or completely substituted by fluorine, and at least one CH2 group of said alkyl is optionally replaced by Oxe2x80x94 or NR23;
R23 is H or alkyl having 1 to 4 carbon atoms, in which alkyl is unsubstituted or partially or completely substituted by fluorine; or
R21 and R22, together with the nitrogen atom to which they are bonded, form a 5-, 6-, or 7-membered ring;
R2, R3, and R4 are, independently of one another, H or F;
R6, R7, R8, and R9 are, independently of one another, H, F, Cl, Br, I, CN, alkyl, or O-alkyl, in which the alkyl groups have 1 to 4 carbon atoms and are unsubstituted or partially or completely substituted by fluorine; or
R6, R7, R8, and R9 are cycloalkyl having 3 to 7 carbon atoms, which is unsubstituted or partially or completely substituted by fluorine; or
R6, R7, R8, and R9 are OH, OCOR24, or NR25R26;
R24 is H or alkyl having 1 to 4 carbon atoms, in which alkyl is unsubstituted or partially or completely substituted by fluorine;
R25 and R26 are, independently of one another, H or alkyl having 1 to 4 carbon atoms, in which alkyl is unsubstituted or partially or completely substituted by fluorine; or
R25 and R26 are COR27; or
R25 and R26, together with the nitrogen atom to which they are bonded, form a 5-, 6-, or 7-membered ring, and at least one CH2 group thereof is optionally replaced by O or NR18;
R27 is H or alkyl having 1 to 4 carbon atoms, in which alkyl is unsubstituted or partially or completely substituted by fluorine; or
a pharmaceutically tolerable salt thereof.
Other embodiments comprise the use of compounds of formula I in which:
R1 and R5 are, independently of one another, H, F, Cl, Br, CN, alkyl having 1 to 4 carbon atoms, CF3, CH2CF3, CF2CF3, cycloalkyl having 3 to 7 carbon atoms, O-alkyl having 1 to 4 carbon atoms, OH, OCF3, OCH2CF3, OCF2CF3, OCOR10, NR11R12, COR13, COOH, COOR14, CONR11R12, xe2x80x94Omxe2x80x94SO2R15, or O-phenyl;
m is 0 or 1;
R10 is H, alkyl having 1 to 4 carbon atoms, CF3, CH2CF3, or CF2CF3;
R11 and R12 are, independently of one another, H, alkyl having 1 to 4 carbon atoms, CF3, CH2CF3, CF2CF3, and at least one CH2 group of said alkyl is optionally replaced by O or NR18; or
R11 and R12, together with the nitrogen atom to which they are bonded, form a 5-, 6-, or 7-membered ring; or
R11 and R12 are COR19 or SO2R20;
R18, R19, and R20 are, independently of one another, H or alkyl having 1 to 4 carbon atoms, CF3, CH2CF3, or CF2CF3;
R13 and R14 are alkyl having 1 to 4 carbon atoms, CF3, CH2CF3, or CF2CF3;
R15 is alkyl having 1 to 4 carbon atoms, CF3, CH2CF3, CF2CF3, OH, O-alkyl having 1 to 4 carbon atoms, OCF3, OCH2CF3, OCF2CF3, or NR21R22;
R21 and R22 are, independently of one another, H, alkyl having 1 to 4 carbon atoms, CF3, CH2CF3, or CF2CF3; or
R21 and R22, together with the nitrogen atom to which they are bonded, are xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)5xe2x80x94, xe2x80x94(CH2)2xe2x80x94Oxe2x80x94(CH2)2xe2x80x94, or xe2x80x94(CH2)2xe2x80x94Nxe2x80x94R30xe2x80x94(CH2)2;
R30 is H, CH3, or CF3;
but R1 and R5 cannot simultaneously be Cl or CH3, and at most one of the substituents R1 and R5 is hydrogen;
R2, R3, and R4 are, independently of one another, H or F;
R6, R7, R8, and R9 are, independently of one another, H, F, Cl, Br, I, CN, alkyl having 1 to 4 carbon atoms, CF3, CH2CF3, CF2CF3, cycloalkyl having 3 to 7 carbon atoms, OH, O-alkyl having 1 to 4 carbon atoms, OCF3, OCH2CF3, OCF2CF3, OCOR24, or NR25R26;
R24 is H, alkyl having 1 to 4 carbon atoms, CF3, CH2CF3, or CF2CF3;
R25 and R26 are, independently of one another, H, alkyl having 1 to 4 carbon atoms, CF3, CH2CF3, CF2CF3, or COR27; or
R25 and R26, together with the nitrogen atom to which they are bonded, form a 5-, 6-, or 7-membered ring;
R27 is H, alkyl having 1 to 4 carbon atoms, CF3, CH2CF3, or CF2CF3; or
a pharmaceutically tolerable salt thereof.
Other embodiments comprise the use of compounds of formula I in which:
R1 and R5 are, independently of one another, H, F, Cl, Br, CN, methyl, ethyl, isopropyl, CF3, cyclopropyl, OH, O-methyl, O-ethyl, O-isopropyl, OCF3, O-acetyl, NH2, N(CH3)2, N(CH2CH3)2, N-pyrrolidino, N-piperidino, N-morpholino, N-(Nxe2x80x2-methyl)-piperazino, NHSO2Me, acetyl, COOH, COOR14, CONR11R12, SO2R15, or O-phenyl;
R11 and R12 are, independently of one another, H, methyl, or ethyl;
R14 is methyl or ethyl;
R15 is CH3, CF3, OH, OCH3, OCF3, or NR21R22;
R21 and R22 are, independently of one another, H or methyl;
but R1 and R5 cannot simultaneously be Cl or CH3, and at most one of the substituents R1 and R5 is hydrogen;
R2,R3,and R4are H;
R6, R7, R8, and R9 are, independently of one another, H, F, Cl, CN, CH3, C2H5, isopropyl, CF3, cyclopropyl, OH, OCH3, OCF3, O-acetyl, or NR25R26;
R25 and R26 are, independently of one another, H, methyl, or acetyl; or
a pharmaceutically tolerable salt thereof.
Another embodiment comprises the use of compounds of formula I in which:
R1 and R5 are, independently of one another, F, Cl, Br, CN, methyl, ethyl, isopropyl, CF3, cyclopropyl, OH, O-methyl, O-ethyl, O-isopropyl, OCF3, O-acetyl, NH2, N(CH3)2, N(CH2CH3)2, N-pyrrolidino, N-piperidino, N-morpholino, N-(Nxe2x80x2-methyl)-piperazino, NHSO2Me, acetyl, COOH, COOR14, CONR11R12, SO2R15, or O-phenyl;
R11 and R12 are, independently of one another, H, methyl, or ethyl;
R14 is methyl or ethyl;
R15 is CH3, CF3, OH, OCH3, OCF3, or NR21R22;
R21 and R22 are, independently of one another, H or methyl;
but R1 and R5 cannot simultaneously be Cl or CH3, and at most one of the substituents R1 and R5 is hydrogen;
R2, R3, and R4 are H;
R6 and R9 are, independently of one another, H, F, Cl, CN, CH3, CF3, cyclopropyl, OH, OCH3, OCF3, O-acetyl, or NR25R26;
R25 and R26 are, independently of one another, H, methyl, or acetyl;
R7 and R8 are, independently of one another, H, F, or OH; or
a pharmaceutically tolerable salt thereof.
Examples comprising the use of compounds of formula I are:
1: (1H-benzimidazol-2-yl)-(2,6-dichlorophenyl)amine;
2: 2-(2,6-dichlorophenylamino)-1H-benzimidazol-4-ol;
3: (1H-benzimidazol-2-yl)-(2,6-dimethylphenyl)amine;
4: (1H-benzimidazol-2-yl)-(2-chloro-6-methylphenyl)amine;
5: (2,6-dichlorophenyl)-(5,6-difluoro-1H-benzimidazol-2-yl)amine;
6: (2,6-dichlorophenyl)-(4-methyl-1H-benzimidazol-2-yl)amine;
7: (1H-benzimidazol-2-yl)-(2-chloro-6-fluorophenyl)amine;
8: (1H-benzimidazol-2-yl)-(2,6-dibromophenyl)amine;
9: 2-(2,6-dichlorophenylamino)-5-fluorobenzimidazole;
10: 2-(2,6-dichlorophenylamino)-4-fluorobenzimidazole;
11: 2-(2-trifluoromethyl-6-chlorophenylamino)benzimidazole;
12: 2-(2,6-dichlorophenylamino)-4,5-difluorobenzimidazole;
13: 2-(2,6-dichlorophenylamino)-5 hydroxybenzimidazole;
14: 2-(2,6-dichlorophenylamino)-4,5,6,7-tetrafluorobenzimidazole;
15: 2-(2,6-dichlorophenylamino)-4,6-difluorobenzimidazole;
16: (1H-benzimidazol-2-yl)-(2-chlorophenyl)amine;
17: (1H-benzimidazol-2-yl)-(2-trifluoromethylphenyl)amine;
18: (1H-benzimidazol-2-yl)-(2-bromophenyl)amine; and
19: (1H-benzimidazol-2-yl)-o-tolylamine; or
a pharmaceutically tolerable salt thereof.
If compounds of formula I contain one or more centers of asymmetry, these can have either the S or the R configuration. The compounds can be present as optical isomers, as diastereomers, as racemates, or as mixtures thereof.
Compounds of formula I can furthermore be present as tautomers or as a mixture of tautomeric structures. In the case of substitution on the corresponding N atoms of the benzimidazole structure, the compounds can be present in the form of the various double bond isomers or as a mixture of the double bond isomers.
The designated alkyl radicals or partially or completely fluorinated alkyl radicals can be either straight-chain or branched.
CH2 units are also the terminal CH3 groups in an alkyl chain, which are interpreted in this connection as CH2xe2x80x94H groups.
The expression xe2x80x9c5-, 6-, or 7-membered ringxe2x80x9d represents a 5-membered to 7-membered heterocyclic ring comprising at least one alkyl or heteroatom. Examples of heteroatoms are nitrogen, oxygen, and sulfur. If multiple heteroatoms are contained, these can be identical or different.
Methods for the preparation of the compounds used are also described. Thus, compounds of formula I can be prepared in the manner known to the person skilled in the art from the underlying isothiocyanates of formula II and the corresponding phenylenediamines of formula III. 
The thiourea intermediately formed here is cyclized to the corresponding compounds of formula I by means of mercury(II) oxide (J. Med. Chem., 18, 90-99 (1975)), methyl iodide (Synthesis, 41-42 (1974)), or carbodiimide (Synthesis, 864-865 (1977)). The isothiocyanates of formula II used here, if not commercially obtainable, can be prepared in the manner known from the literature from the corresponding anilines by the methods known to the person skilled in the art, e.g., by treating with thiophosgene (J. Med. Chem., 18, 90-99 (1975)) or thiocarbonyldiimidazole (Justus Liebigs Ann. Chem., 657 (1962)).
Likewise, starting from the anilines, by treating with NaOH, carbon disulphide, and methyl iodide in processes which are already known from the literature, it is possible to prepare the corresponding N-aryldithiocarbamates (Synthesis, 961 (1981)) and, from these in turn, the N-aryldithiocarboximidates of formula IV (Synthesis, 375 (1983)), which can be reacted in the presence of the phenylenediamines of formula III at elevated temperatures to give the desired compounds of formula I: 
Finally, compounds of formula I can be prepared starting from the anilines and the corresponding 2-substituted benzimidazoles of formula V by heating. 
X in this case is a leaving group, such as, for example, Cl, Br, or SO3H (J. Org. Chem., 51, 1882 (1986)).
British patent specification 1 171 904 describes a general formula which would even allow o,o-disubstitution in the aniline moiety. However, there is no indication of compounds of formula I actually taken into consideration which have an o,o-disubstitution pattern, let alone an experimental description. The compounds described in this British patent specification 1 174 904 are protected therein as substances having antibacterial activity. In the case of compounds according to the invention, it was not possible with the aid of an exemplary compound to detect any antibacterial action, such that the substance class according to British patent specification 1 171 904 can be differentiated clearly from the compounds according to the invention, both structurally and in its pharmacological properties.
Furthermore, some of the benzimidazoles according to the invention could be constructed from WO 9808818, which are described therein as phospholipase inhibitors. However, no single representative of this class of compound is described therein, neither experimentally nor pharmacologically.
It was possible to show that compounds of formula I are outstanding inhibitors of the sodium-hydrogen exchanger (NHE)xe2x80x94in particular, of the sodium-hydrogen exchanger of subtype 3 (NHE3).
On account of these properties, the compounds are suitable for the treatment of diseases which are caused by oxygen deficiency. As a result of their pharmacological properties, the compounds are outstandingly suitable as antiarrhythmic medicaments having a cardioprotective component for infarct prophylaxis and infarct treatment and for the treatment of angina pectoris, which also preventively inhibit or greatly decrease the pathophysiological processes in the formation of ischemically induced damage, in particular, in the triggering of ischemically induced cardiac arrhythmias. Because of their protective actions against pathological hypoxic and ischemic situations, compounds of formula I can be used, as a result of the inhibition of the cellular Na+/H+ exchange mechanism, as medicaments for the treatment of all acute or chronic damage caused by ischemia or diseases induced primarily or secondarily thereby. This relates to their use as medicaments for surgical interventions, e.g., in organ transplants, where the compounds can be used both for the protection of the organs in the donor before and during removal, for the protection of removed organs, for example, during treatment with or storage thereof in physiological fluids, and during surgical transfer to the recipient""s body. The compounds are likewise valuable, protectively acting medicaments when carrying out angioplastic surgical interventions, for example, on the heart and on peripheral vessels. Corresponding to their protective action against ischemically induced damage, the compounds are also suitable as medicaments for the treatment of ischemias of the nervous system, in particular, of the CNS, where they are suitable, for example, for the treatment of stroke or of cerebral edema. Moreover, compounds of formula I used according to the invention are likewise suitable for the treatment of forms of shock, such as, for example, of allergic, cardiogenic, hypovolemic, and of bacterial shock.
Furthermore, the compounds induce an improvement in the respiratory drive and are therefore used for the treatment of respiratory conditions in the following clinical conditions and diseases: disturbed central respiratory drive (e.g., central sleep apneas, sudden infant death, postoperative hypoxia), muscular-related respiratory disorders, respiratory disorders after long-term respiration, respiratory disorders during adaptation in a high mountainous area, obstructive and mixed forms of sleep apnea, and acute and chronic lung diseases with hypoxia and hypercapnia.
The compounds additionally increase the muscle tone of the upper airways such that snoring is suppressed.
A combination of an NHE inhibitor with a carboanhydrase inhibitor (e.g., acetazol-amide), where the latter produces a metabolic acidosis and thereby even increases the respiratory activity, proves advantageous due to increased action and decreased use of active substance.
It has been shown that compounds used according to the invention have a mild laxative action and accordingly can be used advantageously as laxatives or in the case of threatening intestinal blockage, where the prevention of ischemic damage accompanying blockages in the intestinal area is particularly advantageous.
The possibility furthermore exists of preventing gallstone formation.
Moreover, compounds of formula I used according to the invention are distinguished by strong inhibitory action on the proliferation of cells, for example, fibroblast cell proliferation and the proliferation of the vascular smooth muscle cells. Therefore, compounds of formula I are suitable as valuable therapeutics for diseases in which cell proliferation is a primary or secondary cause, and can therefore be used as antiatherosclerotic agents against diabetic late complications, cancers, fibrotic diseases such as pulmonary fibrosis, fibrosis of the liver or fibrosis of the kidneys, and organ hypertrophies and hyperplasias, in particular, in prostate hyperplasia or prostate hypertrophy.
Compounds used according to the invention are effective inhibitors of the cellular sodium-proton antiporter (Na/H exchanger), which is raised in numerous diseases (e.g., essential hypertension, atherosclerosis, diabetes), even in those cells which are accessible to measurements, such as, for example, in erythrocytes, platelets, or leukocytes. Compounds used according to the invention are therefore suitable as outstanding and simple scientific tools, for example, in their use as diagnostics for the determination and differentiation of certain forms of hypertension, but also of atherosclerosis, diabetes, and proliferative diseases. Moreover, compounds of formula I are suitable for preventive therapy for the prevention of the genesis of high blood pressure, for example, of essential hypertension.
It has additionally been found that NHE inhibitors exhibit a favorable influence on the serum lipoproteins. It is generally recognized that for the formation of arteriosclerotic vascular changes, in particular, of a heart disease, excessively high blood lipid levels, xe2x80x98hyperlipoproteinemiaxe2x80x99 is a significant risk factor. For the prophylaxis and the regression of atherosclerotic changes, the lowering of raised serum lipoproteins therefore assumes extreme importance. Compounds used according to the invention can therefore be used for the prophylaxis and for the regression of atherosclerotic changes, by excluding a causal risk factor. With this protection of the vessels against the syndrome of endothelial dysfunction, compounds of formula I are valuable medicaments for the prevention and for the treatment of coronary vasospasms, atherogenesis, and atherosclerosis, left-ventricular hypertrophy and dilated cardiomyopathy, and thrombolytic diseases.
The compounds mentioned are therefore advantageously used for the production of a medicament for the prevention and treatment of sleep apneas and muscle-related respiratory disorders; for the production of a medicament for the prevention and treatment of snoring; for the production of a medicament for lowering blood pressure; for the production of a medicament for the prevention and treatment of diseases which are induced by ischemia and reperfusion of central and peripheral organs, such as, for example, acute kidney failure, stroke, endogenous states of shock, and intestinal diseases; for the production of a medicament for the treatment of diabetic late damage and chronic kidney diseases, in particular, of all kidney inflammations (nephritides) which are associated with increased protein/albumin excretion; for the production of a medicament for the treatment of attack by ectoparasites in human and veterinary medicine; for the production of a medicament for the treatment of the diseases mentioned in combination with blood pressure-lowering substances, typically with angiotensin-converting enzyme (ACE) inhibitors, with diuretics and saluretics such as furosemide, hydrochlorothiazide, pseudoaldosterone antagonists, and aldosterone antagonists, and with angiotensin receptor antagonists.
The administration of sodium-proton exchange inhibitors of formula I as novel medicaments for the lowering of raised blood lipid levels is claimed, and the combination of sodium-proton exchange inhibitors with medicaments having blood pressure-lowering and/or hypolipidemic action.
Typically, the compounds mentioned are advantageously used for the production of a medicament for the prevention and treatment of sleep apneas and muscle-related respiratory disorders; for the production of a medicament for the prevention and treatment of snoring; for the production of a medicament for lowering blood pressure; for the production of a medicament for the prevention and treatment of diseases which are induced by ischemia and reperfusion of central and peripheral organs, such as, for example, acute kidney failure and intestinal diseases; for the production of a medicament for the treatment of diabetic late damage and chronic kidney diseases, in particular, of all kidney inflammations (nephritides) which are associated with increased protein/albumin excretion; for the production of a medicament for the treatment of attack by ectoparasites in human and veterinary medicine; for the production of a medicament for the treatment of the diseases mentioned in combination with blood pressure-lowering substances, preferably with angiotensin-converting enzyme (ACE) inhibitors, with diuretics and saluretics such as furosemide, hydrochlorothiazide, pseudoaldosterone antagonists, and aldosterone antagonists, with adenosine receptor modulators, in particular, with adenosine receptor activators (A2 agonists), and with angiotensin receptor antagonists.
Pharmaceuticals which contain a compound of formula I can in this case be administered orally, parenterally, intravenously, rectally, transdermally, or by inhalation, the administration being dependent on the particular clinical picture of the disease. Compounds of formula I can in this case be administered on their own or together with pharmaceutical excipients, namely both in veterinary and in human medicine.
The person skilled in the art is familiar on the basis of his/her expert knowledge with excipients which are suitable for the desired pharmaceutical formulation. In addition to solvents, gel formers, suppository bases, tablet excipients, and other active compound carriers, it is possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers, or colorants.
For an oral administration form, the active compounds are mixed with the additives suitable therefor, such as vehicles, stabilizers, or inert diluents, and brought by the customary methods into the suitable administration forms, such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic, or oily solutions. Inert excipients which can be used are, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, or starch, in particular, cornstarch. In this case, preparation can be carried out both as dry and moist granules. Suitable oily vehicles or solvents are, for example, vegetable or animal oils, such as sunflower oil or cod liver oil.
For subcutaneous or intravenous administration, the active compounds used, if desired with the substances customary therefor, such as solubilizers, emulsifiers, or further excipients, are brought into solution, suspension, or emulsion. Possible solvents are, for example, water, physiological saline solution, or alcohols (e.g., ethanol, propanol, and glycerol). In addition, other possible solvents are sugar solutions such as glucose or mannitol solutions, or alternatively a mixture of the various solvents mentioned.
Pharmaceutical formulations which are suitable for administration in the form of aerosols or sprays are, for example, solutions, suspensions, or emulsions of the active compound of formula I in a pharmaceutically acceptable solvent, such as, ethanol or water, or a mixture of such solvents.
If required, the formulation can also contain other pharmaceutical excipients such as surfactants, emulsifiers, and stabilizers, and a propellant. Such a preparation customarily contains the active compound in a concentration of approximately 0.1 to 10%, typically, of approximately 0.3 to 3%, by weight.
As used here, treatment includes therapy for a particular disease, such as treating diseases which are influenced by inhibition of the Na+/H+ exchanger. In this respect, treatment can mean successfully eliminating the disease, reducing the effects associated with it, and/or reducing its severity. Treatment also includes prevention or prophylaxis of the onset of a disease by treating patients falling into a risk group or category for developing a particular disease or by treating patients after a successful treatment to prevent reoccurrence of the treated disease. Those skilled in the art can routinely identify patients likely to present with a disease, thereby qualifying as candidates for prevention therapy, because of factors such as diet, habits (e.g., smoking), family history for the disease, etc.
The dose of the active compound of formula I to be administered and the frequency of administration depend on the potency and duration of action of the compounds used; moreover, also on the nature and severity of the illness to be treated and on the sex, age, weight, and individual responsiveness of the mammal to be treated.
On average, the daily dose of a compound of formula I in the case of a patient weighing approximately 75 kg is at least 0.001 mg/kg, typically 0.01 mg/kg, to at most 10 mg/kg, usually 1 mg/kg, of body weight. In the case of acute episodes of the disease, for example, immediately after suffering a cardiac infarct, even higher and especially more frequent doses may also be necessary, e.g., up to 4 individual doses per day. In particular, in the case of i.v. administration, for example, in the case of an infarct patient in the intensive care unit, up to 200 mg per day may be necessary.
Experimental descriptions and examples:
List of abbreviations used:
General:
The retention times (Rt) indicated below relate to LCMS measurements having the following parameters: